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Endosomes as a multifunctional hub to control GPCR function

Award Number: R35GM137835
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Endosomes as a multifunctional hub to control GPCR function - Project Summary Signaling is the fundamental process by which the cell detects and responds to a changing environment. For signaling to function properly, it is necessary for the cell to regulate when and where signaling receptors function. G protein-coupled receptors (GPCRs) are an important family of signaling molecules which, in response to an agonist, activate G proteins to initiate cellular signaling. Classically, G protein signaling and regulation were thought to occur at the plasma membrane. While GPCRs were known to undergo agonist-driven endocytosis and endosomal-lysosomal trafficking, this was largely thought to be a long-term homeostatic mechanism to control GPCR expression. This model has changed dramatically over the last decade. A suite of new biosensors revealed that many GPCRs can activate G proteins at intracellular compartments, including endosomes, and this compartmentalized signaling results in distinct cellular, pharmacological, and physiological outcomes. Compartmentalized GPCR signaling has raised many questions with implications for our understanding of fundamental biology and creation of the next generation of GPCR-targeting therapeutics. Here we will focus on two related questions for compartmentalized GPCR function at the endosome: what proteins regulate GPCR trafficking at the endosome, and how do these regulatory mechanisms affect GPCR signaling and GPCR-drug action? A significant challenge to answering these questions is that it is difficult to identify the endosomal proteins which regulate GPCR signaling and trafficking: many GPCR interacting proteins are low affinity and transient, and this is challenge is compounded with the endosome being a highly compartmentalized organelle. My lab has developed solutions to this problem by developing chemical-biological based tools to identify location- specific GPCR regulatory proteins using proteomics and functional genomics. In the last R35 funding period my lab developed a highly sensitive biosensor for GPCR trafficking through the endosomal-lysosomal pathway, which we combined with functional genomics to identify endosomal proteins which regulate GPCR trafficking. The goal for the next five years is to leverage these discoveries—particularly the finding of a novel endosomal Retromer-based recycling pathway and DNAJC13 as a critical regulator of GPCR sorting at endosomes—to determine the role endosomal sorting proteins play in controlling short- and long-term GPCR-G protein signaling. These studies will define the mechanisms of GPCR signaling and trafficking along the endosomal-lysosomal pathway and lay the foundation for developing improved GPCR-targeting therapeutics.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $429,000 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	6	3/19/2026	COMPETING CONTINUATION	$429,000
														Subtotal = $429,000

Issue Date FY: 2024 ( Subtotal = $384,998 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	5	4/2/2024	NON-COMPETING CONTINUATION	$346,499
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	001	5	5/20/2024	NON-COMPETING CONTINUATION	$38,499
														Subtotal = $384,998

Issue Date FY: 2023 ( Subtotal = $515,859 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	001	4	6/9/2023	SUPPLEMENT FOR EXPANSION	$130,861
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	4	4/20/2023	NON-COMPETING CONTINUATION	$384,998
														Subtotal = $515,859

Issue Date FY: 2022 ( Subtotal = $384,997 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	3	3/30/2022	NON-COMPETING CONTINUATION	$346,495
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	001	3	6/30/2022	NON-COMPETING CONTINUATION	$38,502
														Subtotal = $384,997

Issue Date FY: 2021 ( Subtotal = $384,997 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	2	4/7/2021	NON-COMPETING CONTINUATION	$384,997
														Subtotal = $384,997

Issue Date FY: 2020 ( Subtotal = $384,997 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	1	6/24/2020	NEW	$384,997
														Subtotal = $384,997

Grand Total All Awards = $2,484,848

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Endosomes as a multifunctional hub to control GPCR function

Award Number: R35GM137835

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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